Our long-range goal is to elucidate the mechanisms controlling the excitability of the beta-cell membrane of the pancreatic islets and to determine its role in the recognition of a diversity of molecules and the transduction of this information into a single output, insulin release. To accomplish this, it is our objective to (1) clarify the role of the plasma membrane in maintenance of islet cell function in relation to metabolic events; (2) determine the specific changes in the membrane permeability to the cations, sodium, potassium, and calcium, accompanying electrical responses to a wide-range of agents; (3) assess the role of glucose metabolism in induction of electrical activity; and (4) determine whether groups of cells are coupled to constitute an electrical conducting unit for synchronization of cellular activity. An intracellular microelectrode will be used as a functional probe of individual beta-cells in monolayer cultures of islets. Parallel studies will be made of glucose metabolism and insulin release in order to interpret and guide the electrical studies. The basic knowledge to be gained in pursuit of the above objectives will hopefully aid in determining what possible biophysical abberations lead to the glucose -insensitivity of beta-cells in the diabetic state, and what agents or conditions can be used to ameliorate impaired sensitivity. In addition, any new insight that can be gained concerning maintenance of the functional aspects of cultured beta-cells will aid in obtaining a viable transplantable beta-cell line.